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HX00033561 


FisKE  Fund  Prize  Essay.   No.  LVIII. 


RECENT  CLASSIFICATION 


AND 


TREATMENT  OF  PNEUMONIA, 


MOTTO: 

And  they  shall  beat  their  swords  into 

plowshares,  and  their  spears  into  prun- 

inghooks:  nation  shall  not  lift  up  sword 

against  nation,  neither  shall  they  learn 

WAR  ANY  MORE.  — Isaiah  II:4. 


Author : 
HARRY  S.  BERNTON,  A.  B.,  M.  D. 

Washington,  D.  C. 


Columbia  ^niberfiitp 
intteCitpof^etol^orfe 

CoUese  of  l^f)psimns  anb  ^urgeoniee 


^tltvtntt  Hibrarp 


FisKE  Fund  Prize  Essay.   No.  LVIII. 


RECENT  CLASSIFICATION 

AND 

TREATMENT  OF  PNEUMONIA, 


MOTTO: 

And  they  shall  beat  their  swords  into 
plowshares,  and  their  spears  into  prun- 
inghooks:  nation  shall  not  lift  up  sword 
against  nation,  neither  shall  they  learn 
war  any  more.  —  isaiah  ii :  4. 


Author: 
HARRY  S.  BERNTON,  A.  B.,  M.  D. 

Washington,  D.  C. 


Snow  &  Farnham  Co.,  Printers 

Providence,  R.  I. 

1919 


TTHE  Trustees  of  the  Fiske  Fund,  at  the  annual  meeting  of  the 
•'■  Rhode  Island  Medical  Society,  held  at  Providence,  June  5,  1919, 
announced  that  they  had  awarded  a  premium  of  two  hundred  dollars  to 
an  essay  on  "  Recent  Classification  and  Treatment  of  Pneumonia," 
bearing  the  motto: 

And  they  shall  beat  their  swords  into  plowshares,  and  their  spears  into 
pruninghooks:  nation  shall  not  lift  up  sword  against  nation,  neither  shall 
■  they  learn  war  any  more. — Isaiah  ll:4. 

The  author  was  found  to  be  Harry  S.  Bernton,  A.  B.,  M.D.,of 
Washington,  D.  C. 

DR.  GARDNER  T.  SWARTS,  Providence,  R.  I., 
DR.  JOHN  M.  PETERS,  Providence,  R.  I., 
DR.  JESSE  E.  MOWRY,  Providence,  R.  I., 

Trustees. 

HALSEY  DeWOLF,  M.  D., 

Secretary  of  the  Trustees, 

305  Brook  Street,  Providence,  R.  I. 


Digitized  by  the  Internet  Arciiive 

in  2010  witii  funding  from 

Open  Knowledge  Commons 


http://www.archive.org/details/recentclassificaOObern 


Contents 

page 

Introduction  ....... 

7 

Pneumococcus 

9 

Part  I. 

Basis  of  Classification 
Methods  of  "Typing" 
Type  I      .....          . 

Type  II  and  sub-groups      . 

Type  III 

Type  IV 

Precipitable  Substances 
And  Spinal  Fluids 
Blake's  Optimum  Dilution  Methods    . 
Rapid  Methods  of  "Typing" 

12 

15 
i8 
i8 

20 
21 
21 
24 
28 
29 

Part^II. 

Incidence  of  Types  in  Pneumonia 
Mortality  of  Types  in  Pneumonia 
Incidence  of  Types  in  Children 
Incidence  of  Types  in  Normal  Persons 
Incidence  of  Types  in  Contacts  . 
Incidence  of  Types  in  Convalescents    . 
Occurrence  of  Pneumococcus  in  Dust 
Viability  of  Pneumoccous  in  Sputum  . 

31 

34 
35 
37 
39 

42 

44 
45 

Part  III. 

Sero-therapy  in  Pneumonia 

Production  of  Antipneumococcus  Serum  i    . 

Method  of  Administration  of  Serum    . 

Action  of  Serum         .... 

Results  of  Sero-therapy 

Serum  Reactions        .... 

Endless  Chain  Treatment  . 

Vaccine  Treatment    .... 

Drug  Treatment        .... 

Prophylaxis       ..... 

47 
47 
49 
49 

52 

53 
55 
57 
59 
6o 

Recent  Classification  and  Treatment  of 
Pneumonia 


INTRODUCTION 


The  pneumococcus  is  the  causative  agent  in  more 
cases  of  lobar  pneumonia  than  any  other  micro- 
organism. By  virtue  of  this  fact  the  intensive  study 
of  the  biology  of  the  pneumococcus,  which  the  or- 
ganism merits,  has  yielded  encouraging  results. 
Both  prophylactic  and  therapeutic  measures  have  in 
consequence  been  instituted  which  promise  to  con- 
trol so  ravaging  a  disease.  Pneumonia  exacts  each 
year  a  heavy  toll  in  human  lives  so  that  the  economic 
loss  exceeds  that  of  other  diseases.  The  young  and 
the  old,  the  weak  and  the  strong  are  numbered 
among  its  victims. 

In  this  connection  it  may  not  be  amiss  to  refer  to 
the  mortality  statistics  compiled  by  the  United 
States  Census  Bureau.  In  1916,  98,334  deaths  oc- 
curred from  all  forms  of  pneumonia  in  the  registra- 
tion area  of  the  United  States.  Of  this  number 
54,699  were  due  to  lobar  pneumonia.  The  remain- 
der were  due  to  either  broncho-pneumonia  or  to  an 
unspecified  form  of  the  disease.  The  death  rate  for 
all  forms  of  pneumonia  in  1916  was  137.3  per  100,000 
population.  This  rate  exceeds  that  of  pulmonary 
tuberculosis  by  13.5,  the  death  rate  of  the  latter  being 


8  RECENT  CLASSIFICATION  AND 

123.8  for  the  same  year.  The  following  table  (Table  I) 
shows  that  more  deaths  have  occurred  in  Rhode 
Island  from  pneumonia  than  from  pulmonary  tuber- 
culosis in  the  six-year  period  from  1911  to  1916  in- 
clusive : 

TABLE  I 
Showing  Death  Rate  in  Rhode  Island  per  100,000  Population. 


Year 

From  pneumonia 
(all  forms) 

From  tuberculosis 
of  lungs 

I916 

1590 

142.9 

I915 

164.9 

132.7 

1914 

I43-I 

134.6 

I913 

146.8 

133-4 

I912 

157-7 

132-4 

19II 

152-1 

I45-I 

In  the  city  of  Pittsburgh  alone,  1394  cases  of  the 
disease  were  reported  in  1916,  of  which  1296  proved 
fatal.  The  analysis  by  Shattuck  and  Lawrence  of 
3291  cases  of  lobar  pneumonia,  treated  at  the  Massa- 
chusetts General  Hospital  from  1889  to  1917,  has 
furnished  noteworthy  deductions.  The  authors  have 
noted  a  marked  variation  in  the  yearly  mortality 
rate.  This  reached  as  high  as  40%  in  1896,  and  as 
low  as  16%  in  1906.  The  one  thousand  consecutive 
cases  of  the  disease  at  the  same  hospital,  compiled  by 
Coolidge  and  Townsend,  during  the  period  1882  to 
1889,  have  been  considered  in  addition  to  the  number 
cited.  A  grand  total  of  over  4200  cases  is  thereby 
obtained.  If  of  this  total  the  mortality  rate  is  con- 
sidered by  decades,  it  becomes  evident  that  it  has 
gradually  increased  from  10%  in  the  first  decade  to 
28%  in  1917,  and  that  since  1881  there  has  been  no 


TREATMENT  OF  PNEUMONIA  9 

significant  change  in  the  death  rate.  Acute  lobar 
pneumonia  in  virtue  of  its  prevalence  must  therefore 
be  regarded  as  an  endemic  disease.  The  wide  dis- 
tribution of  the  pneumococcus  and  its  survival  in 
dust  form  two  very  important  factors  in  its  epi- 
demiology. 

The  pneumococcus  was  first  observed  by  Pasteur 
and  Sternberg  in  the  saliva  of  normal  individuals 
about  1881.  Its  association  with  pneumonia  was  es- 
tablished by  Fraenkel  in  1884;  and  later  Weichsel- 
baum  confirmed  the  association  by  demonstrating  its 
presence  in  the  blood  and  in  the  organs  of  victims  of 
the  disease.  After  this  relationship  had  been  es- 
tablished, many  attempts  were  made  to  reproduce  the 
disease  in  animals.  Lamar  and  Meltzer  in  1909  suc- 
cessfully produced  experimental  pneumonia  in  dogs. 
Under  ether  anaesthesia,  a  small  stomach  tube  was 
introduced  through  the  larynx  into  a  bronchus,  and 
from  5  to  10c. c.  of  a  bouillon  culture  of  the  pneu- 
mococcus were  injected  into  the  lung.  The  animals 
were  killed  at  intervals  varying  from  one  to  six  days 
after  the  time  of  injection.  At  autopsy,  consolidation 
involving  one-half  lobe  to  that  of  the  entire  lung  was 
found.  The  pathology  of  the  pulmonic  solidification 
was  identical  with  that  of  lobar  pneumonia  in  human 
beings. 

The  pneumococcus  stains  readily  with  the  aniline 
dyes  and  is  Gram  positive.  It  occurs  in  pairs  of  small 
oval  or  lancet  shaped  organisms,  the  broader  ends  of 
which  are  in  apposition.  During  rapid  growth  ba- 
cillary  forms  occur,  whereas  in  older  cultures  the  or- 


10  RECENT  CLASSIFICATION  AND 

ganism  loses  its  ability  to  stain  by  Gram's  method 
and  involution  forms  appear.  It  is  a  non-motile, 
non-flagellated  form  which  does  not  produce  spores. 
Its  optimum  temperature  is  37°C.,  and  growth  takes 
place  equally  well  under  anaerobic  as  under  aerobic 
conditions. 

The  pneumococcus,  moreover,  when  freshly  iso- 
lated from  human  or  animal  tissues  possesses  a  well 
marked  capsule.  This  is  readily  brought  out  by 
appropriate  staining  methods.  In  fact,  the  excessive 
capsule  development  of  some  forms  of  the  pneumococ- 
cus appears  evident  in  the  ordinary  Gram's  stain 
as  a  halo  around  the  bacterial  cell.  The  organism 
soon  loses  the  capsule  on  cultivation  on  artificial 
media,  but  regains  it  on  being  reinoculated  into  ani- 
mals. It  seems  as  if  the  capsule  serves  as  a  protec- 
tion to  the  microorganism.  Curiously  enough  the 
more  severe  types  of  pneumonia  are  associated  with 
those  organisms  which  show  the  pronounced  capsule 
formation.  Undoubtedly,  they  acquire  thereby  a 
greater  resistance  against  the  immune  forces  of  the 
invaded  host. 

The  simple  laboratory  media  yield  ordinarily  a 
growth  of  the  pneumococcus.  Its  growth,  however, 
is  much  enhanced  by  the  addition  of  serum,  defibri- 
nated  blood,  or  carbohydrate  to  the  medium.  In 
bouillon,  the  pneumococci  grow  diffusely  and  exhibit 
chain  formation.  In  gelatine,  no  liquefaction  takes 
place.  On  blood-agar  plates,  the  appearance  of  the 
pneumococcus  colony  is  definite  and  characteristic. 
The    colony    is    finely   granular,    showing   a   darker 


TREATMENT  OF  PNEUMONIA  11 

centre  and  a  well  defined  border.  It  is,  moreover, 
flat,  transparent,  and  moist  and  presents  a  ringed  or 
wrinkled  appearance.  A  green  zone  of  discoloration 
which  results  from  the  changes  wrought  on  the  hemo- 
globin of  the  red  blood  cells  usually  surrounds  the 
colony.  This  zone  of  methemoglobin  is  accentuated 
by  incubation  of  the  blood  plates  at  ice-box  temper- 
ature. In  media  containing  the  simple  sugars,  an 
initial  growth  of  the  organism  usuajly  takes  place. 
Its  growth  is  soon  retarded  by  the  formation  of  acid, 
in  consequence  of  which  the  organism  dies  out.  The 
acid  producing  power  is  to  be  seen  also  in  the  coagu- 
lation of  litmus  milk  and  of  inulin  serum  water.  The 
ability  to  ferment  inulin  has  been  regarded  as  a  dis- 
tinctive cultural  feature  of  the  pneumococcus.  There 
are  some  strains  which  do  not  possess  this  power,  or 
possess  it  only  temporarily.  Thus  certain  morpho- 
logical and  cultural  characteristics  have  come  to  be 
ascribed  to  the  pneumococcus.  These  do  not  ab- 
solutely distinguish  the  pneumococci  from  the  allied 
group  of  streptococci.  Some  strains  of  the  latter 
may  show  capsule  formation,  produce  acid  in  car- 
bohydrate media,  ferment  inulin,  and  show  a  zone 
of  green  pigmentation  around  the  colony.  Neuf eld's 
observation  in  1900  that  pneumococci  are  soluble  in 
bile  has  proven  of  fundamental  importance.  The 
cholic  acid  is  a  ready  solvent  for  the  pneumococcus, 
but  not  for  the  streptococcus.  The  bile  solubility 
test  furnishes,  therefore,  means  of  absolute  diagnosis 
between  the  pneumococci  and  other  organisms  of 
similar  morphology  and  cultural  characteristics. 


PART   I 


TECHNIQUE 


The  work  of  the  next  decade  (1900-1910)  was 
crowned  with  results  which  radically  affected  the 
older  conceptions  of  pneumonia.  A  new  era  dawned. 
Hitherto  attention  had  been  focussed  on  the  grosser 
relationships  of  organisms.  The  study  of  the  dif- 
ferences between  families  of  microorganisms  now  be- 
came secondary  to  the  study  of  differences  between 
members  of  the  same  family.  It  will  be  recalled  that 
as  early  as  1881  pneumococci  have  been  observed  by 
Sternberg  in  the  saliva  of  normal  individuals.  In 
1909,  Neufeld  and  Handel  have  first  shown  that  im- 
munologic differences  exist  between  pathogenic  and 
non-pathogenic  pneumococci.  Accordingly,  the  re- 
cent biologic  classification  of  the  pneumococcus  has 
been  based  upon  differences  in  immunity  response. 

Many  races  of  pneumococci  were  isolated  from 
cases  of  lobar  pneumonia.  Animals  were  then  im- 
munized by  repeated  injections  with  gradually  in- 
creasing numbers  of  the  organisms.  Thus,  a  rabbit, 
inoculated  repeatedly  with  the  same  strain  of  the 
pneumococcus,  would  show  a  specific  immunity  re- 
sponse against  that  particular  strain.  Herein  was  the 
keystone  of  the  new  classification.  It  has  been  de- 
monstrated that  the  blood  serum  of  an  immunized 


TREATMENT  OF  PNEUMONIA  13 

animal,  horse  or  rabbit,  as  the  case  maybe,  possesses 
the  power  to  agglutinate  in  vitro  that  particular 
strain  of  the  pneumococcus  against  which  it  had  been 
immunized.  Not  only  is  there  a  specific  agglutinin 
present  in  the  immune  serum,  but  also  a  substance 
capable  of  conferring  passive  immunity.  The  viru- 
lence of  the  pneumococcus  for  the  white  mouse  is  an 
interesting  phase  of  its  biology.  Neufeld  and  Handel 
have  demonstrated  that  the  serum  of  a  vaccinated 
animal  protects  a  mouse  against  what  would  other- 
wise be  a  fatal  dose  of  living  pneumococci  of  the 
same  strain. 

The  specific  reaction  consists,  therefore,  in  the  de- 
velopment of  an  agglutinin  and  of  a  protecting  sub- 
stance in  the  serum  of  the  immunized  animal,  both  of 
which  are  specific  for  that  strain  of  the  pneumococcus 
with  which  the  animal  has  been  inoculated.  This 
was  the  predominant  fact  established  by  Neufeld's 
work.  The  entire  subject  was  next  amplified  by 
Cole  and  his  associates  at  the  Rockefeller  Institute. 
Large  numbers  of  pneumococci  have  been  isolated 
from  various  sources  and  animals  immunized  against 
the  strains  isolated.  The  immunity  reactions  of  each 
strain  of  organisms  against  its  homologous  serum 
and  the  other  immune  sera  were  studied.  On  the 
basis  of  protection  tests,  devised  by  Neufeld,  and  of 
the  agglutination  reactions,  Cole  in  1912  divided  the 
pneumococci  into  four  groups.  These  were  desig- 
nated by  him  as  types  I,  II,  III,  and  IV.  Further 
investigation  has  brought  to  light  the  interesting  fact 
that  80%  of  pneumococci  isolated  from  clinical  cases 


14  RECENT  CLASSIFICATION  AND 

of  pneumonia  belong  to  types  I,  II,  and  III;  whereas 
the  remaining  20%  of  pneumonias  are  caused  by 
type  IV.  The  latter  is  the  organism  commonly 
found  in  normal  mouths.  The  organisms  belonging 
to  the  first  three  types  represent  a  group  of  highly 
parasitic  forms  to  which  the  term  "fixed  types"  has 
been  applied.  This  in  contradistinction  to  type  IV, 
which  consists  of  many  heterogeneous  strains.  It 
is  noteworthy  that  the  strain  studied  by  Neufeld 
corresponds  to  type  I  of  the  Rockefeller  classification. 

One  year  later,  in  1913,  Lister  of  South  Africa 
classified  pneumococci  into  twelve  groups,  naming 
them  alphabetically.  Phagocytosis  and  specific  ag- 
glutinations formed  the  basis  of  his  classification. 
Group  A,  numerically  most  important  in  South  Af- 
rica, is  unknown  in  this  country;  and  Lister's  groups 
B,  C,  and  E  are  identical  with  types  II,  I,  and  III 
of  Cole. 

From  the  foregoing  observations  the  following 
summary  is  drawn:  the  serum  of  a  rabbit  im- 
munized against  pneumococcus  type  I  agglutinates 
organisms  of  type  I  in  vitro  and  has  no  effect  on 
types  II,  III,  or  IV;  an  antipneumococcus  serum 
of  type  I  protects  a  mouse  against  a  fatal  dose  of 
type  I  organisms;  whereas  no  protection  is  afforded 
in  case  types  II,  III,  or  IV  organisms  be  used  for  in- 
jection. In  other  words,  there  is  no  cross-agglutina- 
tion and  no  cross-protection. 

The  value  of  the  classification  of  pneumococci 
based  upon  immunologic  differences  is  only  too  ob- 
vious.   Epidemiology,    prophylaxis,    and    treatment 


TREATMENT  OF  PNEUMONIA  IS 

of  acute  infections  are  determined  by  etiology.  It 
is  therefore  of  paramount  importance  to  study  the 
pneumonias  from  the  newer  standpoint.  Much  at- 
tention has  been  given  to  this  phase  of  the  study  by 
laboratory  workers  all  over  the  country.  The  pro- 
gress already  made  augurs  well  for  the  future.  An 
antipneumococcus  serum  against  type  I  has  been 
produced  which,  if  administered  early  in  the  disease, 
affects  the  outcome  favorably.  More  detailed  con- 
sideration is  given  to  the  serum  treatment  of  pneu- 
monia in  another  part  of  this  paper. 

Our  attention  will  now  be  devoted  to  the  methods 
employed  for  the  differentiation  of  the  pneumococci 
into  their  four  types.  Pure  cultures  of  the  organism 
must  first  be  procured  from  the  infected  host.  These 
are  obtainable  from  the  blood  or  sputum  of  the  pa- 
tient or  by  a  direct  lung  puncture.  The  sputum  is 
usually  the  material  at  hand.  Accordingly  it  is  re- 
ceived in  a  sterile  Petri  dish.  The  sputum  from  the 
deeper  air  passages,  freed  from  the  bacterial  flora  of 
the  mouth,  yields  better  results.  A  small  portion  is 
washed  and  ground  and  injected  into  the  peritoneal 
cavity  of  the  white  mouse.  The  mouse  acts  as  a  se- 
lective incubator.  The  pathogenic  pneumococci  mul- 
tiply rapidly,  whereas  the  growth  of  the  saprophytic 
organisms  is  inhibited.  Sufficient  growth  of  the  for- 
mer is  usually  obtained  in  six  to  eight  hours.  Under 
sterile  precautions,  the  peritoneal  cavity  is  opened; 
a  smear  is  made  from  the  exudate  and  a  loopful  of  it 
is  streaked  on  one  half  of  a  blood-agar  plate.  The 
smear,  stained  by  Gram's,  shows  the  character  of  the 


16  RECENT  CLASSIFICATION  AND 

organism  which  has  been  recovered  by  the  inoculation 
method.  As  a  rule,  the  pneumococci  are  present  in 
large  numbers.  By  means  of  a  glass  pipette,  the 
peritoneal  cavity  is  washed  out  with  about  8  to  10c. c. 
of  bouillon  or  salt  solution.  At  this  time  the  presence 
or  absence  of  a  sticky  exudate  between  the  intestinal 
loops  is  noted.  The  peritoneal  washings  containing 
pus  cells  and  bacteria  are  received  in  a  sterile  centri- 
fuge tube.  To  remove  the  pus  cells,  the  tube  is  cen- 
trifugalized  at  low  speed  for  a  few  minutes.  The 
supernatent  fluid  is  pipetted  off  into  another  centri- 
fuge tube.  This  is  revolved  at  high  speed  until  the 
organisms  are  thrown  down.  The  resulting  clear 
supernatent  fluid  was  discarded  in  the  earlier  period 
of  this  work.  It  is  at  present  retained  and  tested 
for  a  specific  soluble  substance  excreted  by  the 
bacterial  bodies. 

The  bacterial  sediment  at  the  bottom  of  the  second 
centrifuge  tube  is  next  emulsified  by  the  addition  of 
a  few  cubic  centimetres  of  salt  solution.  This  con- 
stitutes a  pure  culture  of  the  pneumococcus,  obtained 
during  the  course  of  several  hours  by  animal  inocula- 
tion from  the  sputum  of  a  case  of  pneumonia.  The 
autopsy  of  the  mouse  is  completed  by  opening  the 
thoracic  cavity  and  exposing  the  heart.  As  a  sep- 
ticaemia is  usually  present,  two  or  three  tubes  of 
bouillon  (-|-0.3  to  -j-O.S  acid)  are  inoculated  with  the 
heart's  blood.  A  loopful  of  the  blood  is  finally 
smeared  over  the  second  half  of  the  blood-agar  plate, 
used  previously  for  the  peritoneal  exudate.  These 
are  now  incubated  for  subsequent  examination. 


TREATMENT  OF  PNEUMONIA  17 

Agglutination  tests  are  made  by  mixing  the  saline 
suspension  of  the  pneumococci  with  antisera  i  and  ii 
in  small  sterile  test  tubes.  The  tubes  are  shaken 
gently  and  mixed  by  tapping  with  the  finger.  They 
are  then  placed  in  the  water  bath  at  37°C.  for  two 
hours,  and  afterwards  kept  in  the  ice  box  over  night. 

Soon  after  the  mixing  of  the  suspension  of  the  or- 
ganisms, the  tubes  are  closely  observed  for  reaction. 
This  consists  in  the  clumping  of  the  organisms  so 
that  at  first  small  flakes  appear,  as  in  a  "miniature 
snowstorm."  On  standing,  the  clumps  settle  to  the 
bottom  of  the  test  tube.  If  the  organism  belongs  to 
type  II,  the  clumping  reaction  in  the  No.  2  will  be 
seen  in  one  or  two  minutes.  The  reaction  of  type  I 
organisms  to  their  homologous  serum  is  slower,  the 
clumps  appearing  within  half  an  hour.  The  presence 
of  clumps  in  either  tube  No.  1  or  tube  No.  2  deter- 
mines to  which  of  the  two  types  the  organism  belongs. 
In  the  absence  of  clumping,  the  diagnosis  of  type  III 
is  justified  in  case  a  sticky  exudate  has  been  found  at 
autopsy  and  in  case  smears  from  the  peritoneal  cavity 
show  the  organism  to  possess  a  large  capsule.  The 
diagnosis  of  type  IV  is  reached  by  a  process  of 
exclusion. 

The  tubes  are  again  observed  and  the  reactions 
read  after  the  ice-box  incubation  over  night.  On 
the  next  day,  also,  the  bouillon  cultures,  made  from 
the  heart's  blood,  are  examined.  If  they  are  pure 
cultures  of  the  pneumococcus,  tubes  of  litmus  milk 
and  inulin  serum  water  are  inoculated  with  the 
growth,    The  acid   production  in  these  media  fur- 


18  RECENT  CLASSIFICATION  AND 

nishes  confirmatory  evidence  of  the  cultural  charac- 
teristics of  the  pneumococcus.  Agglutination  and 
bile  solubility  tests  are  repeated  with  the  bouillon 
growth. 

The  foregoing  technique  makes  possible  the  prompt 
isolation  of  the  strain  of  pneumococcus  from  the  sputa 
of  pneumonia  patients  and  the  determination  of  the 
type  of  infecting  organisms  by  agglutination  tests.  A 
consideration  of  the  four  types  is  essential  for  an  ap- 
preciation of  the  problems  involved  in  the  epidemi- 
ology and  therapeusis  of  the  disease.  The  biologic 
differences  between  the  four  types  are  most  striking. 

Pneumococcus  type  I,  the  first  member  under  dis- 
cussion, has  the  distinguishing  capsule  of  the  pneu- 
mococcus group.  The  capsule,  however,  is  not  as 
well  developed  as  it  is  in  types  II  and  III.  This 
may  account  for  the  success  which  has  attended  the 
production  of  an  antipneumococcic  serum  against 
the  homologous  organism.  This  serum,  as  will  be  in- 
dicated later,  is  of  distinct  value  in  the  treatment  of 
pneumonia  caused  by  type  I.  Such  a  serum  care- 
fully prepared  will  agglutinate  type  I  organisms  in  a 
dilution  of  1:400  or  over,  and  0.2c.c.  will  protect  a 
mouse  against  0.1c. c.  of  a  virulent  culture.  Thestand- 
ard  of  virulence  is  determined  by  the  least  possible 
amount  of  a  bouillon  culture  which  will  kill  a  white- 
mouse  in  less  than  36  hours.  The  amount  consists  of 
O.OOOOOlc.c. 

The  agglutinating  and  protecting  powers  of  an 
antipneumococcus  serum  against  type  II  organisms 
are   less   effective.    Despite   identical    methods   em- 


TREATMENT  OF  PNEUMONIA  19 

ployed  in  immunizing  animals  with  type  II  organ- 
isms, the  results  markedly  differ.  Thus  an  anti- 
pneumococcic  serum  type  II  agglutinates  the  homol- 
ogous organisms  in  dilutions  no  greater  than  1 :200 
and  0.2c.c.  affords  protection  against  only  O.Olc.c.  of  a 
virulent  culture.  The  antiserum  I  is,  therefore,  ten 
times  more  powerful  than  antiserum  II.  Experi- 
ments, moreover,  have  proven  the  inadequacy  of 
type  II  antiserum  in  treatment. 

In  the  description  of  methods  of  "typing"  it  has 
been  noted  that  agglutination  takes  place  promptly 
upon  the  addition  of  anitserum  II  to  tube  No.  2 
containing  the  organisms.  As  the  number  of  tests 
increased,  the  observation  has  been  made  that  some 
of  the  type  II  pneumococci  become  agglutinated 
slowly.  These  have  been  termed  "atypical  11 's." 
Not  only  is  their  agglutinating  response  delayed,  but 
their  virulence  is  slightly  less  than  that  of  the  typical 
members  of  the  group.  In  1915,  Avery  published 
his  classification  of  the  atypical  II  organisms,  which 
was  based  on  a  study  of  ten  strains.  The  ten  strains 
have  been  divided  into  sub-groups:  I  la,  lib,  and 
llx,  respectively. 

In  the  four  years  following  Avery's  work,  Stillman 
has  applied  similar  methods  of  study  to  a  larger 
series  of  atypical  II  organisms,  204  in  number.  These 
strains  have  all  shown  the  delayed  agglutination  with 
antiserum  II.  The  strains  have  been  obtained  from 
the  most  varied  sources,  and  include  77  from  cases 
of  lobar  pneumonia,  5  from  post-operative  pneu- 
monias, 100  from  normal  mouths,  10  from  convales- 


20  RECENT  CLASSIFICATION  AND 

cents,  and  6  from  dust.  By  means  of  specific  ag- 
glutinins, Stillman  in  1919  has  classified  the  atypical 
II  pneumococci  into  twelve  sub-groups.  Sub-group 
lib  is  the  largest,  comprising  39%  of  all  strains 
studied.  Sub-groups  I  la  and  Ilh  are  essentially  the 
pathogenic  forms.  Of  the  458  strains  of  pneumococci, 
isolated  from  cases  of  pneumonia  at  the  Rockefeller 
Hospital  in  three  years,  52  or  11%  belong  to  atypical 
II  forms.  In  the  59  cases  of  atypical  II  pneumonias, 
there  were  18  deaths  or  32%.  In  summary  it  may  be 
stated  that  the  twelve  sub-groups  of  atypical  11 's 
have  an  incidence  of  11%  in  lobar  pneumonia  and 
18%  in  normal  mouths,  and  that  the  mortality  of 
the  former  cases  is  32%,  indicating  their  high 
pathogenicity. 

It  will  be  recalled  that  the  diagnosis  of  pneumo- 
coccus  type  III  is  made  on  morphologic  grounds. 
The  organism  is  larger,  rounder,  and  less  lanceolate 
than  the  members  of  the  other  groups.  It  possesses, 
moreover,  a  very  large  capsule,  and  the  inflammatory 
exudate  which  it  produces  is  of  a  mucoid  character. 
Until  1915,  the  diagnosis  of  tpye  III  by  agglutina- 
tion test  was  impossible,  because  no  antiserum  was 
available.  In  August  of  that  year,  Wardsworth  and 
Kirkbride  had  succeeded  in  actively  immunizing 
horses  against  pneumococcus  type  III.  The  task 
is  most  difiicult,  it  being  necessary  to  remove  the 
sticky  capsule  from  the  organism  by  treatment  with 
weak  acids.  The  contribution  in  this  regard  has  been 
most  noteworthy,  for  the  diagnosis  of  type  III  can 
now  be  made  on  a  serologic  basis  with  every  assurance 


TREATMENT  OF  PNEUMONIA  21 

of  positivity.  Subsequent  experience  has  shown  that 
mucoid  exudates  are  formed  also  by  some  members 
of  types  II  and  IV.  In  my  series,  one  atypical  II 
and  one  type  IV  showed  a  definite  stringy  exudate 
in  the  peritoneal  cavity  of  the  mouse.  Undoubtedly 
such  organisms  form  connecting  links  between  the 
various  members  of  the  pneumococcus  family.  The 
converse  of  this  also  obtains,  in  that  some  type  III 
organisms  produce  no  mucoid  exudate.  During  the 
influenza  epidemic,  I  isolated  one  strain  from  a 
case  of  pneumonia  which  agglutinated  promptly 
with  antiserum  III,  and  yet  the  peritoneal  cavity  of 
the  mouse  was  devoid  of  the  mucoid  exudate. 

Type  IV  represents  all  the  remaining  members  of 
the  pneumococcus  family.  It  is  the  group  commonly 
encountered  in  normal  mouths  and  is  responsible  for 
about  20%  of  all  pneumococcic  pneumonias.  The 
group  is  characterized  by  much  heterogeneity  and 
has  been  most  extensively  studied  by  Olmstead.  The 
study  has  embraced  the  immunologic  relationships 
of  94  strains  —  46  from  normal  mouths  and  48  from 
varied  sources.  Thirty-seven  immune  monovalent 
sera  have  been  prepared.  At  least  twelve  sub- 
groups have  been  identified,  the  members  of  which 
show  cross-agglutination  with  each  other  but  not 
with  the  other  groups.  Undoubtedly  some  members 
of  the  group  are  transition  forms  between  type  IIx 
and  type  IV. 

In  1917,  Dochez  and  Avery  have  added  another 
noteworthy  contribution  to  the  biology  of  the  pneu- 
mococcus.   The  authors  have  observed  that  a  soluble 


22  RECENT  CLASSIFICATION  AND 

substance  is  excreted  by  the  actively  growing  or- 
ganism into  the  surrounding  culture  medium.  This 
substance  is  of  a  protein  character  and  is  precipitated 
by  the  specific  antiserum.  In  cases  of  pneumonia,  it 
is  found  in  the  circulating  blood  and  is  eliminated 
from  the  patient  through  the  kidneys.  Type  III 
produces  the  largest  amount  of  soluble  substance,  and 
types  II  and  I  come  next  in  the  order  named.  The 
determination  of  type  may  be  made,  therefore,  by  the 
examination  of  the  urine.  An  equal  amount  of  each 
of  the  pneumococcic  anitsera  (0.5c.c.)  is  added  to 
each  of  three  tubes  containing  the  patient's  urine. 
The  diagnosis  of  type  is  determined  by  which  of 
the  antisera  produces  a  coagulum. 

The  production  of  the  soluble  substance  takes 
place  early  in  the  course  of  the  disease.  Its  presence 
has  been  demonstrated  in  the  urine  as  early  as  twelve 
hours  after  the  initial  chill.  Its  excretion  may  be 
continued  for  many  days  during  convalescence.  In 
some  cases  the  prolonged  excretion  by  the  kidneys 
has  been  associated  with  an  unresolved  pneumonia. 
Obviously  the  production  of  the  soluble  and  pre- 
cipitable  substance  is  directly  proportional  to  the 
amount  of  infection.  Moreover,  it  is  also  of  grave 
prognostic  significance,  for  the  mortality  is  high  in 
those  cases  of  pneumonia  which  show  its  presence  in 
the  urine.  The  most  virulent  strains  of  the  pneu- 
mococci  are  more  apt  to  produce  the  soluble  pre- 
cipitinogen. 

Quigley  disagrees  with  the  deductions  drawn  by 
Dochez   and   Avery.    The   former   investigator   has 


TREATMENT  OF  PNEUMONIA  23 

studied  the  precipitin  reactions  in  the  urine  of  100 
cases  of  lobar  pneumonia.  The  incidence  of  type  is 
as  follows:  Type  I,  33  cases;  type  II,  36  cases; 
type  III,  13  cases;  and  type  IV,  18  cases.  His 
findings  are  of  timely  interest.  Of  the  82  cases  due 
to  the  fixed  types,  the  urine  of  67  (81%)  have 
given  at  some  time  during  the  disease  the  specific 
precipitin  reaction.  Of  the  67  cases,  23  or  34%  have 
died.  The  strength  of  the  reaction  has  gradually  in- 
creased for  a  period  of  3  to  4  days,  persisted  from  2 
to  19  days,  and  gradually  waned.  Of  the  27  deaths 
due  to  the  fixed  types,  23  have  shown  the  reaction 
in  the  urine.  Four  have  been  negative.  It  thus 
appears  that  the  precipitinogen  is  present  in  the 
urine  of  a  large  percentage  of  fatal  cases  of  pneu- 
monia ;  but  the  mortality  of  those  patients  who  have 
not  shown  the  precipitinogen  in  the  urine  has  been 
only  slightly  less  than  in  those  who  show  its  presence. 
The  excretion  of  a  soluble  substance  by  the  pneu- 
mococcus  during  its  period  of  growth  has  proven  of 
the  greatest  value  in  diagnostic  technique.  This  sub- 
stance is  present  wherever  the  organisms  find  favor- 
able conditions  for  growth, — in  the  lung,  in  the 
pleural,  synovial,  or  spinal  fluids,  or  in  the  peritoneal 
cavity  of  the  mouse.  It  will  be  recalled  that  the 
pneumococcus  multiplies  rapidly  in  the  mouse  after 
the  injection  of  washed  sputum;  and  that  for  diag- 
nosis of  type,  the  cavity  is  washed  out  with  a  saline 
solution.  After  the  removal  of  the  pus  cells  by  slow 
centrifugalization,  the  supernatent  contains  only  the 
organisms.    Upon    high    centrifugalization,    the    or- 


24  RECENT  CLASSIFICATION  AND 

ganisms  are  thrown  down,  leaving  a  clear,  supernatent 
fluid.  This  fluid  has  formerly  been  discarded.  In 
the  present  technique,  the  fluid  is  retained  and 
tested  for  the  presence  of  the  soluble  specific  pre- 
cipitinogen. Equal  amounts  of  the  three  specific 
antisera  are  added  to  each  of  three  tubes  containing 
the  clear,  supernatent  liquid.  A  precipitate  forms 
promptly  in  the  tube  upon  the  addition  of  its  homol- 
ogous antiserum.  This  test  is  done  at  the  same  time 
that  the  agglutination  reactions  are  performed  with 
the  emulsion  made  from  the  sediment  of  pneu- 
mococci.  The  precipitin  test  acts,  therefore,  as  a 
control  for  the  agglutination  test.  It  has,  moreover, 
certain  advantages  in  that  the  precipitin  test  demands 
no  incubation  and  is  not  interfered  with  by  the  pres- 
ence of  other  organisms.  It  is  specific  and  shows  no 
cross-reactions.  If  a  mouse,  inoculated  with  sputum 
for  diagnosis,  dies  during  the  early  hours  of  the  morn- 
ing, considerable  autolysis  may  take  place  before 
it  comes  to  autopsy.  The  pneumococci  become  con- 
taminated with  saprophytic  invaders,  making  clear- 
cut  agglutination  tests  impossible.  On  such  occa- 
sions, the  precipitin  reaction  ofl^ers  means  for  prompt 
diagnosis  of  type.  As  previously  stated,  the  presence 
of  contaminating  bacteria  does  not  interfere  with  the 
precipitinogen.  Its  presence  can  be  detected  after 
all  the  organisms  have  been  removed  by  centrifugal- 
ization. 

Three  opportunities  have  come  to  me  for  making 
rapid  diagnosis  of  types  in  spinal  fluids  from  cases  of 
pneumococcic    meningitis.    The    fluids    upon    with- 


TREATMENT  OF  PNEUMONIA  25 

drawal  were  turbid.  Stained  smears  showed  the 
presence  of  pus  cells  and  Gram  positive  diplococci. 
The  fluids  were  centrifugalized  long  enough  to  yield 
a  clear  supernatent  portion  and  a  sediment  of  pus 
cells  and  organisms.  With  the  former  portion,  the 
precipitin  test  was  performed  by  adding  the  specific 
antisera.  The  reaction  was  obtained  almost  in- 
stantaneously. One  spinal  fluid  showed  a  type  III, 
and  the  two  others  gave  a  type  I  reaction.  The  diag- 
nosis of  type  was  confirmed  by  inoculating  mice  with 
the  sediment  of  organisms  which  were  thrown  down 
in  the  centrifugalizing  tubes.  The  presence  of  the 
soluble  precipitinogen  in  the  spinal  fluids  of  pneu- 
mococcal meningitis  has  not  been  entirely  unexpected. 
The  spinal  fluid  is  an  ideal  medium  to  receive  the 
soluble  products  which  result  from  the  metabolism 
of  the  invading  pneumococci.  The  conditions  are 
analogous  to  those  which  obtain  in  the  peritoneal 
cavity  of  the  mouse  or  in  a  test  tube  of  bouillon.  In 
fact,  one  case  of  meningitis  comes  to  mind  in  which 
the  spinal  fluid  has  served  as  liquid  culture  medium 
for  the  pneumococcus.  So  overwhelming  was  the  in- 
fection that  no  pus  cells,  the  first  line  of  defense,  had 
been  called  forth.  I  have  seen  other  cases  of  menin- 
gitis in  which  most  diligent  search  failed  to  reveal 
the  presence  of  bacteria  in  the  purulent  sediment. 
Pneumococci,  however,  were  obtained  in  cultures 
from  the  same  sediment. 

It  is,  doubtless,  apparent  that  in  lobar  pneumonia 
the  rapidly  multiplying  pneumococci  secrete  a  soluble 
substance  into  the  lung  alveoli;    that  this  substance 


26  RECENT  CLASSIFICATION  AND 

is  taken  up  by  the  capillaries  and  lymph  vessels  and 
is  circulated  through  the  blood  stream;  and  that 
eventually  the  soluble  precipitinogen  is  excreted  by 
the  kidneys  and  its  presence  is  detected  by  the  ex- 
amination of  the  urine.  The  question  which  now 
suggests  itself  is  whether  or  not  the  soluble  precipi- 
tinogen is  found  in  the  spinal  fluids  of  those  cases  of 
pneumonia  which  are  uncomplicated  by  any  in- 
flammatory meningitis.  Not  infrequently  in  syphi- 
lis, the  syphilitic  antibody  is  present  both  in  the 
blood  and  in  the  cerebro-spinal  fluid,  as  determined 
by  the  Wassermann  reaction.  It  may  be  present 
in  the  spinal  fluids  of  those  cases  in  which  there  are 
no  symptoms  referable  to  involvement  of  the  cerebro- 
spinal axis.  The  mere  absence  of  symptoms,  how- 
ever, does  not  exclude  the  possibility  of  a  pathological 
lesion  of  the  nervous  system.  The  conclusion  may 
be  warranted  that  in  some  cases  of  syphilis  there  is  a 
passive  transfer  of  the  antibody  from  the  blood  stream 
into  the  cerebro-spinal  fluid.  In  the  light  of  the 
above  facts,  the  question  may  be  asked,  "Does  a 
similar  transfer  of  soluble  precipitinogen  take  place 
from  the  blood  to  the  spinal  fluid  in  the  course  of  a 
pneumonia?" 

In  my  experience,  I  have  encountered  one  case  of 
pneumonia  due  to  a  type  I  infection  which  in  part 
answers  the  question.  The  disease  ran  a  very  severe 
course.  A  purulent  arthritis  of  the  knee  was  an  early 
complication,  from  which  the  type  I  pneumococcus 
was  isolated.  Several  hours  prior  to  death,  symp- 
toms of  meningitis  presented  themselves.    Lumbar 


TREATMENT  OF  PNEUMONIA  27 

puncture  yielded  a  large  amount  of  a  clear  fluid. 
The  globulin  test  was  negative,  and  there  was  no 
excess  of  cellular  elements.  It  was  obviously  a  case 
of  meningismus.  On  testing  the  undiluted  fluid  with 
each  of  the  three  antipneumococcic  sera,  no  pre- 
cipitin reaction  was  obtained.  It  follows,  therefore, 
that  in  this  case  at  least  there  was  no  passive  trans- 
fer from  the  blood  to  the  spinal  fluid  of  the  soluble 
precipitinogen.  The  severe  course  of  the  pneumonia 
with  its  septicaemic  manifestations  justifies  the  be- 
lief that  the  precipitinogen  must  have  been  present 
in  the  blood  stream,  and  yet  none  was  detected  in  the 
spinal  fluid.  The  problem  now  assumes  a  physiologi- 
cal aspect.  Despite  the  excessive  production  of 
spinal  fluid,  was  the  choroid  plexus  impermeable  to 
the  precipitinogen  or  was  the  capillary  pressure  too 
high  to  admit  of  the  passage  of  the  precipitinogen 
from  the  blood  stream  into  the  cerebro-spinal  fluid? 
Whatever  factors  may  be  involved,  the  spinal  fluids 
of  pneumonia  cases  are  deserving  of  study.  The  con- 
centration of  the  precipitinogen  in  the  blood  stream, 
the  pressure  of  the  cerebral  capillaries,  the  presence  or 
absence  of  pneumococcal  precipitinogen  in  the  spinal 
fluid,  the  permeability  or  impermeability  of  the 
choroid  plexus  may  furnish  evidence  concerning  the 
physiological  mechanism  of  so  formidable  a  disease. 
Any  description  of  technique  for  the  determination 
of  type  is  incomplete  without  mention  of  Blake's 
modification.  Blake,  in  1917,  has  devised  a  means 
for  overcoming  a  difliculty  which  has  been  encoun- 
tered in  the  agglutination  tests.    Some  forms  of  pneu- 


28  RECENT  CLASSIFICATION  AND 

mococci  represent  transitions  between  the  various 
types,  and  accordingly  show  agglutination  in  all  the 
antipneumococcic  sera.  The  character  of  the  ag- 
glutination is  atypical.  It  takes  place  more  slowly 
and  is  less  complete  than  in  the  agglutination  re- 
actions seen  with  the  "fixed  types." 

To  render  cross-agglutination  impossible,  Blake 
has  established  an  optimum  dilution  of  the  antisera 
and  an  optimum  incubation  time.  The  use  of  the 
antisera  undiluted,  as  has  been  the  practice  hitherto, 
has  been  dispensed  with.  Antiserum  I  is  now  used  in 
the  dilution  of  1:20;  antiserum  II  is  used  both  un- 
diluted and  diluted  1:20;  and  antiserum  III  in  the 
dilution  of  1:5.  Equal  parts  (O.Sc.c.)  of  the  suspen- 
sion of  organisms  are  added  to  the  dilutions  of  the 
antisera,  and  the  tubes  are  incubated  in  the  water 
bath  at  37°C.  for  one  hour.  At  the  end  of  that  time, 
the  agglutination  of  the  organisms  is  complete  in 
the  homologous  antiserum.  The  following  table 
(Table  II)  indicates  the  agglutination  reactions  of 
the  different  types  of  pneumococci,  resulting  from  the 
use  of  diluted  antisera,  as  suggested  by  Blake: 

TABLE  II 
Showing  Blake's  Optimum  Dilution  Method 


Antiserum  I  Antiserum  II                         Antiserum  III 

i:20  undUuted  1 :20  1:5 

Type  I                       ++  —  —  — 

Type  II                       —  ++  +-I-  — 

Type  II  (a,  b,  x)       —  +  —  — 

Type  III                     —  —  —  +-I- 

Type  IV                      —  —  —  — 


TREATMENT  OF  PNEUMONIA  29 

It  is  evident  that  the  typical  II  forms  can  be 
readily  differentiated  from  the  atypical.  The  former 
clump  in  the  diluted  and  undiluted  homologous  an- 
tiserum. The  latter  show,  at  the  end  of  one  hour, 
partial  to  complete  clumping  only  in  undiluted  serum. 
The  use  of  the  diluted  antisera,  as  seen  in  the  above 
table,  makes  cross-agglutination  impossible  with 
transition  forms,  and  makes  diagnosis  of  type  more 
exact. 

The  determination  of  type  of  pneumococcus  in 
cases  of  lobar  pneumonia  is  of  practical  importance. 
The  efficacy  of  antipneumococcus  serum  I  in  therapy 
depends  upon  its  early  administration.  In  any  acute 
self-limited  infection,  treatment  must  be  begun  as 
soon  as  possible  to  be  of  any  avail.  Each  hour 
counts.  The  minimal  time  for  diagnosis  of  type  by 
mouse  inoculation  varies  from  8  to  12  hours.  Methods 
have,  therefore,  been  introduced  whereby  the  diag- 
nosis of  type  may  be  made  more  promptly.  Mitchell 
and  Muns,  in  1917,  and  Krumurede  and  Valentine 
in  1918  have  proposed  shorter  methods.  These  de- 
pend upon  the  presence  in  the  sputum  of  the  soluble 
precipitinogen,  which  is  formed  in  whatever  medium 
pneumococci  find  favorable  conditions  for  growth. 

Avery,  in  1918,  has  devised  a  rapid  cultural 
method  for  the  pneumococcus.  It  emphasizes  some 
fundamental  characteristics  of  the  pneumococcus  — 
that  the  addition  of  carbohydrate  and  blood  protein 
to  culture  medium  encourages  an  initial  growth  of 
the  organism;  that  bile  acts  as  a  ready  solvent  for 
the  pneumococcus;  and  that  a  soluble  precipitinogen 


30  RECENT  CLASSIFICATION  AND  TREATMENT 

is  formed  during  the  period  of  vigorous  growth. 
Avery  has  controlled  the  diagnosis  of  type  by  the 
above  rapid  cultural  method  with  the  mouse  inocu- 
lation method,  and  in  60  cases  the  results  have  been 
identical. 


PART   II 


STATISTICS  —  EPIDEMIOLOGY 


As  a  sequence  to  the  recognition  of  types  amongst 
the  pneumococci,  their  relative  incidence  in  pneu- 
monia becomes  an  interesting  subject  for  investiga- 
tion. The  experiences  at  the  Rockefeller  Hospital 
furnish  the  earlier  estimates.  Thus,  in  the  year  1912- 
1913,  74  cases  of  pneumonia  have  been  studied. 
The  incidence  of  type  has  been  as  follows: 

Type  I  35  cases  or  47% 

Type  II  13      "     or  18% 

Type  III  10      "     or  13% 

Type  IV  16      "     or  22% 

In  the  year  1913-1914,  71  cases  of  pneumonia  have 
been  treated  at  the  institution.  These  have  been 
classified  as  follows: 

Type  I  21  cases  or  30% 

Type  II  28      "or  39%^ 

Type  III  6      "     or    8%, 

Type  IV  16      "     or  23% 

It  appears,  therefore,  that  in  the  first  series  58  cases 
or  78%  have  been  caused  by  the  "fixed  types"  (I 
to  III  inclusive),  whereas  16  cases  or  22%  have  been 
due  to  type  IV.  This  percentage  closely  corresponds 
with  that  of  the  second  series,  77%  due  to  the  "fixed 


32 


RECENT  CLASSIFICATION  AND 


types"  and  23%  to  type  IV.  The  constancy  of  the 
percentage  findings  is  most  noteworthy.  Three  years 
later,  Cole,  in  reviewing  his  greatly  enlarged  experience, 
concludes  that  60  to  70%  of  cases  of  lobar  pneu- 
monia are  caused  by  types  I  and  II;  10  to  15%  by 
type  III;  and  20  to  25%  by  type  IV.  To  control 
Cole's  observations  the  following  table  has  been 
compiled,  which  contains  the  results  of  different  in- 
vestigators in  different  parts  of  the  country: 


TABLE 

III 

Showing  Type 

Incidence 

Investigators 

Location 

I 

II 

II 
a,  b, 

III 

X. 

IV 

Total 

Alexander  & 

Boston, 

Christian 

Mass. 

25 

22 

12 

45 

104 

Author 

[R.  L] 

24 

22 

15 

89 

150 

Beals  &  Others 

Mich. 

27 

25 

49 

lOI 

Blanton  &  Irons 

Mich. 

II 

16 

16 

148 

191 

Cole 

Texas 

17 

3 

4 

I 

6 

31 

Cole  &  Others 

Rockefeller 

Hospital 

151 

133 

19 

59 

92 

454 

Dick 

Arkansas 

6 

10 

I 

12 

29 

Hartman  & 

Lacy 

Pittsburgh 

41 

29 

6 

23 

99 

Kirkbride 

N.  Y.  State 

102 

39 

13 

56 

119 

329 

Litchfield 

Western  Penn. 

55 

39 

7 

33 

134 

McLelland 

Alexandria,  La. 

•    13 

4 

I 

24 

42 

Medalia  & 

Schiff 

Waco,  Tex. 

6 

13 

19 

38 

Mitchell  & 

Syracuse, 

Muns 

N.  Y. 

19 

4 

3 

4 

29 

59 

Quigley 

Chicago 

33 

36 

13 

18 

100 

Thomas 

Camp  Mead, 

Md. 

57 

26 

II 

27 

121 

Total 

587 

421 

50 

191 

733 

1982 

TREATMENT  OF  PNEUMONIA  33 

The  incidence  of  types  based  on  the  above  study 
of  1982  cases  of  pneumonia  in  widely  scattered  sec- 
tions is  as  follows : 

Type  I  29.6+% 

Type  II  21.2+% 

Type  II  (atypical)  2.5+% 
Type  III  9.6+% 

Type  IV  36.9+% 

The  occurrence  of  the  "fixed  types"  is  less  than  that 
of  Cole's  earlier  estimate,  notably  so  in  types  II  and 

III.  The  most  striking  discrepancy  is  seen  in  type 

IV,  the  percentage  of  which  equals  36.9  as  com- 
pared with  the  20  to  25  percentage  incidence  noted 
by  Cole.  In  two  localities,  the  incidence  of  type  IV 
reached  as  high  as  45%  and  50.8%,  in  Camp  Pike, 
Arkansas,  and  Camp  Upton,  New  York,  respectively. 
Pneumococcus  type  IV,  it  will  be  remembered,  is 
the  organism  found  normally  in  the  upper  respiratory 
passages.  This  observation  is  not  without  an  im- 
portant bearing  on  epidemiology,  as  will  be  dis- 
cussed later. 

The  mortality  rate  of  the  four  types  is  of  equal 
interest  with  their  incidence.  The  following  table 
shows  their  percentage  mortality,  as  determined  by 
the  several  investigators : 


34  RECENT  CLASSIFICATION  AND 

TABLE  IV 
Showing    Mortality-rate   of   the   Four   Types   of    Pneumococci 


No.  of 

Investigators                               cases 

I 

II 

II 
a,  b, 

X. 

III 

IV 

Alexander  &  Christian        104 

32.0% 

40-9% 

50.0% 

24.4% 

Hartman  &  Lacy                   99 

38.0% 

34-0% 

67.0% 

26.0% 

Litchfield                              134 

47-0% 

41.0% 

57-0% 

48.0% 

McLelland                              42 

7.7% 

25-0% 

4-2% 

Medalia  &  SchifT                   38 

7.0% 

5.0% 

Quigley                                   100 

39-0% 

36.0% 

8.0% 

170% 

Thomas                                 1 2 1 

5-3% 

19-2% 

18.: 

2% 

22.2% 

Total             638 

Average 

28.1% 

29.0% 

18.: 

2% 

45-5% 

20.9% 

Of  the  638  cases  of  pneumonia,  therefore,  the  mor- 
tality rate  has  been  28.1%  in  type  I  cases;  29.2% 
in  type  II;  18.2%  in  type  II  atypical;  45.5%  in 
type  III;  and  20.9%  in  type  IV  cases.  The  above 
percentages  of  deaths  due  to  the  fixed  types  are  in 
accord  with  the  earlier  findings  of  Cole.  He  has 
estimated  that  the  mortality  of  types  I  and  II  equals 
25  to  30%;  of  type  III,  50%  or  more;  and  of  type  IV, 
10  to  15%.  In  the  two  compilations,  the  highest 
death  rate  is  maintained  by  type  III  infections. 
Type  IV  infections,  as  a  result  of  this  study,  do  not 
warrant  the  favorable  prognosis  which  has  been  ac- 
corded them.  Their  percentage  mortality  reaches 
20.9  as  compared  with  15%,  given  by  Cole. 

Many  observers  have  called  attention  to  the  fact 
that  the  mortality  of  the  different  types  of  pneumonia 
varies  in  different  years,  more  notably  in  type  IV, 
and  less  so  in  the  fixed  types.  Bovaird  mentions 
a  mortality  of  5%  in  1914  in  pneumonias  due  to 
type  IV,   and  a   mortality  of  25%  in  1916  caused 


TREATMENT  OF  PNEUMONIA  35 

by  the  same  type.  Litchfield  cites  a  case  of  pneu- 
mococcic  meningitis,  compHcating  a  pneumonia  due 
to  type  IV.  My  series  includes  fourteen  cases  of 
lobar  pneumonia  following  measles.  Pneumococcus 
type  IV  has  been  isolated  from  each  case.  The 
disease  ran  a  very  severe  course  and  was  accom- 
panied with  a  high  mortality.  The  opinion  originally 
maintained  concerning  the  favorable  prognostic  sig- 
nificance of  type  IV  in  pneumonia  needs  be  modified. 
The  type  of  pneumococci  occurring  in  the  pneu- 
monias of  infants  and  children  merit  investigation, 
for  the  disease  is  less  fatal  in  the  young  than  in 
adults.  Pisek  and  Pease  have,  in  1916,  published 
the  following  results  of  their  study  of  48  cases  of 
pneumonia  in  children  under  six  years  of  age: 

TABLE  V 

Types  of  Pneumococci  occurring  in  Children 

(From  Pisek  and  Pease) 


Cases  of 

Lobar 

Pneumonia 

Cases  of 
Broncho- 
Pneumonia 

Percentage 

Pn,  I 

9 

2 

22.9 

Pn.  II 

II 

3 

293 

Pn.  Ill 

I 

3 

8.3 

Pn.  IV 

7 

12 

39-8 

Dunn  has  also  found  type  IV  to  be  the  predomina- 
ting organism.  Mitchell  has  classified  the  pneu- 
mococci in  90  cases  of  pneumonia  which  have  oc- 
curred during  the  winters  1914-1915  and  1915-1916. 
The  average  age  of  the  90  children  has  been  2  years 


36  RECENT  CLASSIFICATION  AND 

and  3  months.  Six  of  the  children  have  been  over  6 
years  of  age,  and  62  under  2  years.  The  frequency 
of  types  has  been  as  follows: 

Type  I  11.1% 

Type  II  11.1% 

Type  III  ?>.?>% 

Type  IV  74.4% 

I  have  isolated  pneumococcus  type  I  from  a  child  of 
5  years,  and  type  IV  from  2  children  aged  2,  from 
one  aged  6,  and  from  one  aged  8.  Compared  with 
the  percentage  incidence  of  80  of  the  "fixed  types" 
in  adults,  that  of  children  reaches  only  25.5%  as 
shown  by  Mitchell.  The  mortality  percentage  of 
the  types  in  Mitchell's  series  has  been: 

Type  I  no  deaths 

Type  II  20% 

Type  III  ^Z.?>% 

Type  IV  10.9% 

The  above  findings  warrant  the  conclusion  that  pneu- 
mococcus type  IV  occurs  more  frequently  in  the 
pneumonias  of  infants  and  children  than  of  adults, 
and  that  the  mortality  of  the  fixed  types  is  lower  in 
infants  than  it  is  in  adults. 

From  the  point  of  view  of  epidemiology,  there  is  no 
disease  which  is  better  understood  than  diphtheria. 
Four  important  factors  are  recognized  as  operative  in 
its  spread:  first,  the  presence  of  the  diphtheria  ba- 
cillus in  normal  individuals;  second,  the  presence  of 
the  organism  in  those  exposed  to  patients  or  to  con- 


TREATMENT  OF  PNEUMONIA  37 

valescents  from  the  disease;  third,  the  "carrier" 
stage  of  convalescents;  and  fourth,  the  transmission 
of  the  bacillus  by  food  substance,  as  milk,  ice  cream, 
etc.  Are  the  same  factors  operative  in  pneumonia  as 
in  diphtheria?  In  answer  to  this  important  question, 
it  becomes  necessary  first  to  consider  the  incidence 
of  the  four  types  of  pneumococci  in  healthy  persons. 

Stillman,  in  1916,  has  presented  the  results  of  his 
study  of  the  types  of  pneumococci  present  in  the 
sputum  of  normal  individuals.  The  mouse  inocula- 
tion method,  as  previously  described,  was  employed. 
Of  398  normal  persons,  pneumococci  have  been  ab- 
sent in  226,  and  found  present  in  the  sputa  of  172. 
Of  the  latter  number,  the  type  distribution  has  been 
as  follows.     See  Table  VI. 

The  results  of  the  study  of  another  series  of  healthy 
persons,  appearing  one  year  later,  in  1917,  have 
proved  confirmatory.  Of  297  individuals  pneumo- 
cocci have  been  isolated  from  116,  with  the  following 
grouping : 

TABLES  VI  AND  VII 

Incidence  of  Pneumococci  in  Normal  Persons 
(From  Stillman) 


Incidence 

Percentage 

Incidence 

Percentage 

Type  I 

4 

2.16 

I 

0.8 

Type  II 

4 

2.l6 

0 

0.0 

Type  I  la 

o 

o.o 

I 

0.8 

Type  lib 

II 

5-84 

7 

5.8 

Type  IIx 

15 

7-79 

14 

11.6 

Type  III 

44 

23.40 

34 

28.1 

Type  IV 

no 

58.51 

64 

52.9 

38  RECENT  CLASSIFICATION  AND 

The  high  incidence  of  type  III  and  type  IV  in  normal 
persons  is  most  striking  as  compared  with  the  low 
incidence  of  types  I  and  II.  Type  III  is  more  com- 
mon in  the  mouth  than  has  formerly  been  supposed. 
The  incidence  of  types  III  and  IV  in  disease  is 
represented  by  a  percentage  of  10  and  36  respectively. 
The  conclusion,  therefore,  becomes  justifiable  that 
pneumonias  due  to  types  III  and  IV  are  autogenic 
in  character.  The  organisms  live  in  the  upper  res- 
piratory passages  as  saprophytes  until  the  balance  of 
power  between  the  host  and  potential  invaders  is 
disturbed.  The  cause  of  the  disturbance  may  be 
attributed  to  a  lowered  resistance.  This  explanation, 
however,  is  unsatisfactory.  Measures  may  be  de- 
vised for  determining  the  immunity  or  susceptibility 
of  the  individual  to  pneumococcic  infection  by  some 
simple  method,  as  the  Schick  cutaneous  test  in  diph- 
theria. Certainly  investigation  along  these  lines 
may  be  productive  of  valuable  information. 

The  study  of  the  bacteriology  of  post-operative 
pneumonias  and  of  common  colds  lends  support  to 
the  autogenic  theory  of  type  III  and  type  IV  infections. 
Olmstead  in  a  study  of  130  cases  of  post-operative 
pneumonia  has  isolated  pneumococci  in  28  instances. 
The  types  occurring  amongst  them  are  as  follows: 

Incidence  Percentage 

Type  I  2  cases  or    7.1% 

Type  II  1  case    or    3.5% 

Type  II  (atypical)  2  cases  or    7.1% 

Type  III  5     "      or  17.8% 

Type  IV  18     "      or  64.2% 


TREATMENT  OF  PNEUMONIA  39 

Similar  observation  has  been  made  in  forty-three 
cases  of  "common  colds"  with  the  following  result; 

Incidence  Percentage 

Type  I  2  cases  or    4.6 

Type  II  2      "      or    4.6 

Type  III  4     "      or    9.3 

Type  IV  35     "     or  81.3 

The  percentage  of  types  III  and  IV  continues  as 
consistently  high  in  autogenic  infections  as  under 
normal  conditions  of  health. 

The  striking  fact  remains  that  the  incidence  of 
both  types  I  and  II  in  normal  individuals  is  low  (0.8 
to  11.6%),  whereas  in  disease  the  two  types  comprise 
50  to  55%  of  all  cases  of  lobar  pneumonia.  Some  ex- 
planation other  than  autogenic  infection  must  be 
made.  The  alternative  is  infection  from  without. 
Therefore  the  transmissibility  of  the  fixed  types  of 
pneumococci  from  patients  infected  to  those  in  con- 
tact with  them  needs  be  ascertained.  Information 
in  this  regard  has  first  been  obtained  from  the  in- 
vestigations of  Dochez  and  Avery  in  1915.  Thirteen 
associates  of  thirty  patients  suffering  from  pneu- 
monia, have  proved  to  be  carriers  of  the  identical 
types  of  pneumococci  which  were  responsible  for  the 
infection.  Thus,  eight  cases  of  pneumonia  due  to 
type  I  gave  rise  to  three  positive  contacts,  each  one 
of  the  latter  having  in  the  sputum  a  type  I  pneumo- 
coccus.  The  same  was  true  of  24  cases  of  pneu- 
monia due  to  type  II.  They  gave  rise  to  ten  car- 
riers of  type   II   amongst  their  contacts.    Stillman 


40  RECENT  CLASSIFICATION  AND 

has  studied  the  contacts  of  48  pneumonia  cases 
during  the  winter  1915-1916,  with  the  following 
results: 

Type  I  —  24  cases ;   contacts  44,  of  whom  two 
proved  positive,  8.3% 

Type  II —  17  cases;    contacts  40,  of  whom 
three  proved  positive,  17.6% 

Accordingly,  5  of  the  84  contacts  or  5.9%  became 
carriers  of  the  fixed  types  of  pneumococci. 

In  1917,  Stillman  repeated  the  study.  He  found 
that  of  107  normal  persons  exposed  to  cases  of  type 
I  pneumonia,  15%  showed  pneumococcus  type  I;  of 
77  exposed  to  type  II  cases,  5  or  6%  showed  type  II. 
Accordingly  11%  of  persons  coming  in  contact  with 
cases  of  lobar  pneumonia  harbored  in  the  saliva  the 
fixed  types  of  pneumococci;  whereas  of  297  in- 
dividuals who  were  not  exposed  only  0.8%  were  car- 
riers. Furthermore,  15  cases  of  lobar  pneumonia  out 
of  a  total  of  52  due  to  types  I  and  II  were  responsible 
for  one  or  more  carriers  amongst  their  associates. 
Examination  of  the  184  persons  who  lived  in  the  52 
households  of  the  pneumonia  patients,  showed  a  car- 
rier state  of  types  I  and  II  in  21  individuals  or  11% 
of  the  total  number. 

The  foregoing  experiences  emphasize  the  import- 
ance of  "contact"  as  a  factor  in  the  spread  of  pneu- 
monia.   This  is  well  illustrated  by   a  series    of    six 


TREATMENT  OF  PNEUMONIA  41 

cases  of  lobar  pneumonia  in  one  household,  which 
has  been  recorded  by  Berry  and  Chickering.  There 
were  six  persons,  all  related,  occupying  the  same 
dwelling.  On  May  13,  1916,  Mrs.  D.,  age  34,  de- 
veloped pneumonia  and  died  11  days  later,  on  May 
24.  The  other  members  in  the  following  sequence 
developed  the  disease:  May  14,  Gertrude  D.,  age  4; 
May  18,  Mabel  D.,  age  14;  May  19,  Arthur  D., 
age  6;  May  19,  Fred  D.,  age  20  months;  and  on 
May  22,  Floyd  D.,  age  11  years.  Pneumococcus 
type  I  was  isolated  from  five  of  the  patients.  Un- 
questionably, this  represents  infection  with  the 
same  type  of  organism,  spread  by  contact  from  one 
member  of  the  family  to  another. 

I  have  studied  the  mouth  flora  of  twelve  contacts 
with  four  cases  of  pneumonia  caused  by  type  I. 
None  of  the  contacts  proved  positive.  My  series, 
however,  is  too  small  to  permit  of  any  deductions. 
In  support  of  the  newer  view  of  infection  by  contact, 
the  incidence  of  pneumococcus  types  in  rural  dis- 
tricts furnishes  interesting  evidence.  Richardson  has 
analyzed  the  types  of  46  cases  of  lobar  pneumonia 
in  country  communities  and  has  compared  his  find- 
ings with  the  type-incidence  of  the  disease  in  the 
city.    The  following  table  shows  the  comparison: 


No.  of  cases 

Percentage 

Average  percentage 

of  Penn.  Hospital 

cases 

Type  I 

7 

15.2 

28.6 

Type  II 

5 

10.8 

21,2 

Type  III 

2 

4.3 

8.3 

Type  IV 

32 

69.6 

41.8 

42  RECENT  CLASSIFICATION  AND 

The  chance  for  infection  by  contact  is  obviously 
less  in  sparse!}^  settled  communities  than  in  the 
centres  of  population.  The  high  percentage  of  type 
IV  infection,  which  is  autogenic  in  character,  is  in 
accord  with  expectations.  Four  of  the  type  I  cases 
and  two  of  the  type  II  cases  give  a  history  of  a  visit 
to  the  city  prior  to  the  onset  of  the  disease.  This 
suggests  the  possibility  of  having  acquired  the  fixed 
types  of  pneumococci  where  opportunities  for  con- 
tact are  greater. 

Of  equal  importance  with  the  presence  of  the  fixed 
types  in  "contacts"  with  pneumonia  patients  is  their 
presence  in  convalescents  from  the  disease.  The 
persistence  of  diphtheria  bacilli  in  the  throat  after 
all  clinical  symptoms  have  disappeared  is  a  con- 
dition which  may  present  itself  with  any  patient. 
The  same  holds  true  of  the  typhoid  bacillus,  which 
may  be  discharged  for  months  in  the  stools  and  urine 
of  convalescents.  The  work  of  Dochez,  Avery,  and 
Stillman  has  shown  that  "carriers"  may  also  be  found 
in  convalescents  from  pneumonia  caused  by  the 
fixed  types  of  pneumococci.  In  a  study  of  53  cases, 
it  has  been  determined  that  the  shortest  carrying 
period  is  seven  days,  and  the  longest  85  days;  and 
that  the  average  carrying  period  for  type  I  is  25 
days  and  for  type  II  it  is  43  days. 

My  observations  in  this  regard  have  been  as 
follows : 


TREATMENT  OF  PNEUMONIA 


43 


Case  No. 

Type  of 
Pneumococcus 

Number  of  days 

after 
onset  of  disease 

Type  of  Pneu- 
mococcus during 
convalescence 

I 

II 

21 

no  pneumococci 

2 

I 

3 

22 

3 

I 

I8 

IV 

4 

I 

27 

II 

5 

I 

2 

5 

IV 

6 

III 

4 
8 

23 

III 
III 
III 

7 

I 

3 

7 

8 

I 

3 

14 

25 

9 

I 

35 
54 

72 
102 
251 

IV 

no    pneumococci 

lO 

I 

26 

I  from  nasal  swabs 
IV  from  saliva 

Cases  No.  5  and  No.  9  represent  the  shortest  and 
the  longest  carrying  periods  of  5  and  102  days  re- 
spectively. The  persistence  of  type  III  in  case  No. 
6  for  23  days  after  the  onset  is  consistent  with  the 
autogenic  character  of  type  III  pneumonia.  Case 
No.  10  is  of  unusual  interest.  On  the  26th  day  after 
the  onset  of  the  disease,  when  convalescence  was 
well  advanced,  swabs  were  rubbed  over  the  nasal 
mucosa  of  each  side  and  then  soaked  in  bouillon. 
Some  of  the  bouillon  was  injected  intraperitoneally 
in  the  mouse.  Type  I  pneumococcus  was  isolated 
from  each  swab.  At  the  same  time  the  sputum  was 
injected  and  a  type  IV  pneumococcus  was  recovered. 


44  RECENT  CLASSIFICATION  AND 

On  other  occasions  I  have  recovered  from  the  nasal 
mucosa  a  fixed  type  of  pneumococcus  similar  to  the 
one  found  in  the  sputum.  It  is  conceivable  that 
more  positive  findings  may  be  obtained  by  the  use  of 
a  West  tube  in  procuring  organisms  from  the  naso- 
pharyngeal mucosa.  This  method  may  furnish  a 
more  critical  index  of  the  bacterial  flora  than  is  pro- 
cured from  the  saliva  of  healthy  persons  or  of  con- 
valescents. 

Thus  far,  it  has  been  indicated  that  "fixed  types" 
pneumococci  are  transmitted  from  person  to  per- 
son by  direct  contact.  "Is  there  any  intermediary 
agent?"  is  a  question  which  must  now  engage  the 
attention.  Stillman  in  1917  has  shown  that  dust 
may  carry  pathogenic  pneumococci.  Hitherto  bac- 
teriological investigations  of  dust  have  been  re- 
stricted to  cultural  methods.  Stillman  has  made  ob- 
servations of  far-reaching  importance  by  utilizing 
animal-inoculation  methods  in  this  study.  Dust  of 
rooms  has  been  collected  in  sterile  bouillon  and  in- 
jected into  mice.  In  this  manner  the  dust  of  60 
rooms  has  been  examined  and  in  18  of  them  or  29% 
pneumococci  have  been  recovered.  The  types  of 
pneumococci  correspond  to  those  found  normally  in 
the  mouth.  In  the  dust  of  one  room,  however,  a 
type  I  had  been  encountered.  Curiously  enough,  a 
carrier  of  pneumococcus  type  I  had  visited  in  that 
room.  The  dust  of  183  households,  in  which  cases 
of  pneumonia  due  to  types  I  and  II  have  occurred, 
has  similarly  been  examined.  Pneumococci  have 
been  found  present  in  74  or  40%  of  that  number. 


TREATMENT  OF  PNEUMONIA  45 

Type  I  has  been  isolated  from  the  dust  of  25  rooms, 
and  type  II  from  23  rooms.  Rooms  in  the  house- 
holds other  than  those  which  the  patients  have  oc- 
cupied have  also  had  pneumococci  of  the  fixed  types 
in  their  dust. 

There  are  two  epidemics  on  record  which  em- 
phasize the  importance  of  dust  as  a  factor.  Of 
six  cases  of  pneumonia  in  a  Boys'  Asylum,  3  or  50% 
have  been  caused  by  type  I.  The  same  type  of  or- 
ganism has  been  isolated  not  only  from  10%  of 
healthy  contacts  (56  in  number),  but  also  from  the 
dust  of  the  dormitory.  The  second  outbreak  oc- 
curred in  a  ward  at  the  Rochester  State  Hospital  for 
the  Insane.  Of  six  cases  of  lobar  pneumonia,  four 
were  caused  by  type  I.  Two  per  cent  of  healthy  con- 
tacts (148  in  number)  and  the  dust  collected  from 
the  ward,  have  also  yielded  pneumococcus  type  I. 

Pneumococci  may  even  remain  viable  in  the  sputum 
from  patients  for  several  days.  The  necessity  of  dis- 
infecting the  sputum  from  active  cases  of  pneumo- 
nia is  emphasized  by  the  following  experience:  On 
a  handkerchief,  I  received  a  specimen  of  sputum  from 
a  pneumonia  patient,  who  was  infected  with  a  type 
I  organism.  I  placed  the  handkerchief  behind  a 
picture  which  was  hung  on  the  wall  in  the  patient's 
room.  Six  days  later,  I  excised  a  portion  on  which 
the  sputum  had  dried  and  soaked  it  in  bouillon.  I 
then  inoculated  a  mouse  with  some  of  the  bouillon. 
Type  I  pneumococcus  was  recovered.  On  the  eighth 
day  I  repeated  the  observation,  and  again  isolated 
the   type    I    organism.    It   is   noteworthy   that   the 


46  RECENT  CLASSIFICATION  AND  TREATMENT 

second  mouse  died  five  days  after  the  injection.  Ap- 
parently the  organism,  though  viable,  had  become 
less  virulent.  No  further  tests  were  possible.  This 
single  experiment,  however,  points  out  the  danger 
which  may  result  from  the  improper  disposal  of  the 
sputum  from  active  cases,  as  well  as  from  careless 
spitting.  Pneumococci,  despite  the  effects  of  drying, 
retain  their  viability  not  only  in  sputum,  but  also  in 
the  dust  of  households. 

The  deductions  based  on  the  foregoing  considera- 
tions of  the  factors  concerned  in  the  epidemiology  of 
lobar  pneumonia  are: 

Pneumonias  due  to  types  III  and  IV  are  auto- 
genic, for  both  types  are  found  in  the  mouth 
flora  of  normal  persons.  Infections  with  type  I 
and  II  may  result  from  direct  contact  with  an 
active  case,  or  with  a  convalescent,  or  with  a 
healthy  carrier  of  those  types;  and  from  indirect 
contact,  as  an  air-borne  infection  from  dust  or 
dried  sputum. 


PART   III 


TREATMENT 


Coincident  with  the  increase  in  knowledge  of  the 
etiology  of  pneumonia  has  come  an  advance  in  the 
therapeusis  of  the  disease.  Serum-therapy  has  ac- 
cordingly been  suggested  by  the  earlier  clinical  and 
laboratory  experiences  as  a  means  for  combatting  so 
acute  an  infection.  Passive  immunity,  conferred 
upon  the  host  as  a  protection  against  the  parasite, 
has  proven  effective  in  diphtheria,  tetanus,  menin- 
gococcus meningitis,  and  gas-bacillus  infection.  Sim- 
ilarly, an  antiserum  has  been  devised  for  therapeutic 
use  against  pneumococcal  infections  caused  by 
type  I.  The  antisera  produced  against  types  II  and 
III  have  thus  far  been  of  no  avail  in  treatment. 
Further  investigations  will  undoubtedly  overcome  the 
subtle  causes  for  failure  with  these  two  antisera. 

The  therapeutic  serum  is  obtained  from  the  horse 
after  a  course  of  active  immunization.  The  first  in- 
jections consist  of  washed  culture  sediment  of 
fresh  18-hour  cultures  of  type  I  organisms  which  are 
killed  by  heat.  Three  such  injections  are  adminis- 
tered on  three  successive  days;  these  are  followed 
by  increasing  doses  of  living  organisms.  After  an 
interval  of  one  week,  the  series  of  injections  is  re- 
peated. Six  days  after  the  second  injection,  the 
animal  is  bled.    Anderson  has  modified  this  technique 


48  RECENT  CLASSIFICATION  AND 

by  administering  six  daily  injections  in  three  courses 
with  seven-day  intervals. 

The  potency  of  the  serum  thus  obtained  is  de- 
termined by  protection  tests  on  mice.  A  serum,  to 
warrant  its  use  in  therapy,  must  be  of  such  potency 
that  0.1c. c.  will  protect  a  mouse  against  0.4c.c.  of  cul- 
ture, which  would  be  fatal  in  0. 000001c. c.  A  serum 
of  low  potency  is  disappointing  in  its  results.  This  is 
illustrated  by  Spooner  and  Sellards.  Before  the  in- 
fluenza epidemic,  they  treated  with  an  antiserum  of 
low  titre  24  cases  of  pneumonia  caused  by  type  I. 
Of  the  24  patients,  19  recovered  and  5  died,  yielding 
a  mortality  of  20%.  During  the  epidemic,  54  cases 
were  treated  with  the  same  serum.  In  this  number 
there  were  31  recoveries  and  23  deaths,  a  mortality 
of  43%.  During  the  height  of  the  epidemic,  15 
cases  were  treated  with  a  serum  of  standard  titre. 
The  results  proved  most  satisfactory.  Of  the  15 
treated  cases,  only  one  case  died,  giving  a  mortality 
of  7%.  The  fatal  case  was  moribund  at  time  of 
treatment. 

Curiously  enough,  agglutination  tests  applied  to 
antipneumococcic  serum  furnish  inconclusive  evi- 
dence of  its  therapeutic  value.  Ordinarily  a  serum 
of  high  agglutinin  titre  has  little  protective  power; 
and  conversely,  as  emphasized  by  McCoy,  a  serum 
of  high  protective  power  may  have  no  agglutinins. 

For  effective  therapeutic  use  in  pneumonia  caused 
by  type  I,  not  only  is  it  essential  that  the  serum  be  of 
standard  potency,  but  it  must  also  be  administered 
as  early  in  the  disease  as  is  possible.    Herein  lies  the 


TREATMENT  OF  PNEUMONIA  49 

importance  of  prompt  diagnosis  of  type.  The  meth- 
ods of  diagnosis  by  examination  of  the  sputum  and 
urine  of  the  patient  have  already  been  discussed  in 
detail.  The  antiserum,  75  to  100c. c.  in  amount,  is 
administered  intravenously.  This  is  repeated  every 
six  to  eight  hours  until  a  favorable  result  is  obtained. 
The  average  dosage  consists  of  250c. c.  Within  an 
hour  or  two  after  the  administration  of  the  serum,  a 
slight  elevation  of  temperature  usually  precedes  a 
marked  fall.  A  second  rise  in  temperature  is  an  in- 
dication for  more  serum.  Temperature  records  are 
to  be  made  every  two  hours. 

Patients  who  are  treated  on  the  second  or  third  day 
of  their  disease  rarely  require  more  than  three  doses 
of  serum.  In  treated  cases,  crises  are  more  frequent 
on  the  second,  third, or  fourth  day.  The  febrile  period 
is  shortened.  The  antiserum,  moreover,  acts  as  an 
agent  in  sterilizing  the  patient's  blood  and  in  pre- 
venting the  development  of  septicaemic  complica- 
tions. In  the  severer  infections,  pneumococci  varying 
in  number  from  900  to  2  per  cubic  centimetre  may 
be  present  in  the  blood  stream.  The  antiserum  also 
produces  agglutinins  in  the  blood  of  the  patient. 
Soon  after  the  administration  of  the  antiserum,  the 
patient's  blood  may  agglutinate  the  pneumococci  in 
the  dilution  of  1:10.  With  the  rise  in  the  agglutinin 
index,  there  is  a  fall  in  temperature.  The  presence, 
however,  of  agglutinins  in  the  patient  is  no  criterion 
as  to  the  effectiveness  of  serum-therapy  or  as  to  prog- 
nosis. As  has  been  shown  by  Bloomfield,  fatal 
cases  of  pneumonia  have  had  agglutinins  of  high  titre 


50  RECENT  CLASSIFICATION  AND 

in  the  blood ;  whereas  cases  with  a  favorable  outcome 
have  had  a  transient  agglutinin  power  or  none  at  all. 
One  of  my  cases  confirms  the  experience  of  Bloom- 
field.  No  agglutinins  were  demonstrable  in  the  blood 
after  the  serum  treatment,  yet  the  patient  made  a 
prompt  recovery  from  the  disease.  It  would  be  of 
theoretical  interest,  at  least,  to  determine  to  what 
extent  the  protective  bodies  of  the  antiserum  are 
absorbed  by  the  patient's  blood.  A  better  guide 
of  efficacy  in  treatment  may  thereby  be  obtained. 
To  what  factors  may,  then,  the  curative  value  of  the 
antipneumococcic  serum  be  attributed?  The  work 
of  Stryker,  to  which  reference  has  been  made,  shows 
the  effects  of  specific  immune  serum  upon  pneu- 
mococci  of  homologous  type  in  vitro.  It  will  be  re- 
called that  pneumococci  grown  in  media  to  which 
immune  serum  has  been  added,  lose  their  capsule  and 
virulence.  Their  growth  is  unaffected,  for  the  im- 
mune serum  has  no  bacteriocidal  action  in  vitro. 
Immune  serum  administered  intravenously,  how- 
ever, is  possessed  of  bacteriocidal  properties.  Sterili- 
zation of  the  blood  in  pneumonia  patients  usually  re- 
sults from  this  procedure.  Explanation  of  the  mech- 
anism of  sterilization  is  gained  by  experimental 
evidence.  A  rabbit  receives  in  one  ear  vein  an  in- 
jection of  pneumococci,  and  one  minute  later  re- 
ceives a  dose  of  antipneumococcic  serum  in  the  vein 
of  the  opposite  ear.  The  effect  first  noted  is  the  im- 
mediate clumping  of  all  the  organisms  in  the  blood 
and  the  removal  of  the  clumps  by  the  spleen,  liver, 
and   lungs.    Active   phagocytosis   now  ensues.    The 


TREATMENT  OF  PNEUMONIA  51 

polymorphonuclear  leucocytes  are  chiefly  engaged, 
and  their  activity  is  directed  towards  the  clumps.  A 
single  leucocyte  may  contain  50  to  100  diplococci; 
and  as  the  result  of  the  digestion  of  the  bacteria  by 
the  blood  cells  within  the  organs  of  the  body,  steri- 
lization of  the  blood  is  accomplished. 

It  becomes  necessary,  therefore,  to  administer  in 
the  course  of  treatment  sufficient  antiserum  to  ag- 
glutinate and  sensitize  the  bacteria  and  to  render 
them  harmless.  Another  requirement  for  successful 
treatment  is  the  use  of  sufficiently  large  amounts  of 
serum  to  neutralize  in  addition  the  soluble  anti- 
genic substances  formed  by  the  pneumococci.  These 
substances  circulating  in  the  blood  stream  have  the 
power  to  fix  the  antibodies  of  the  immune  serum.  In 
consequence,  there  is  less  antiserum  available  for 
the  sensitization  and  agglutination  of  the  bacteria. 
The  earlier  in  the  disease  the  antipneumococcic 
serum  is  administered,  the  more  effective  is  the  con- 
trol of  the  infection  made  possible.  In  the  very 
severe  infections  or  late  in  the  infection,  the  soluble 
antigenic  substances  may  be  present  to  such  an 
extent  as  to  require  impracticably  large  amounts  of 
serum  for  their  neutralization.  Moreover,  these  sub- 
stances, resulting  from  bacterial  metabolism,  need 
to  be  saturated  before  there  can  be  any  effective 
concentration  of  antibodies  in  the  blood  stream. 
The  presence  of  the  soluble  antigenic  substances  and 
their  effects  on  immune  sera  can  readily  be  demon- 
strated. Some  pleural  fluid  from  a  case  of  empyema 
due  to  fixed  type  of  pneumococcus  is  centrifuged. 


52  RECENT  CLASSIFICATION  AND 

The  organisms  are  removed  and  the  sterility 
of  the  supernatent  fluid  is  determined  by  cultural 
methods.  This  bacterial  free  fluid,  added  to  anti- 
pneumococcic  serum,  not  only  lowers  the  agglutinin 
index  of  the  latter  against  its  homologous  organism, 
but  also  diminishes  its  protective  power,  as  de- 
termined by  mouse  inoculation.  There  must  conse- 
quently be  present  some  substances  in  the  exudate 
which  are  capable  of  abstracting  or  neutralizing 
some  of  the  immune  bodies  of  the  antiserum.  These 
specific  substances  are  also  present  in  the  blood  in 
cases  of  severe  septicaemia.  Their  presence  may  ac- 
count for  the  failure  of  antipneumococcic  serum  in 
the  treatment  of  empyema  by  direct  injection  into 
the  pleural  cavity;  and  even  in  the  treatment  of 
pneumococcic  meningitis.  Litchfield  reports  twelve 
cases  of  meningitis  complicating  pneumonia  due  to 
type  I.  Despite  the  intraspinous  administration  of 
the  serum,  there  were  no  recoveries. 

Consideration  must  now  be  given  to  the  value  of 
antipneumococcic  serum  type  I  in  the  treatment  of 
pneumonia.  Final  judgment  will  of  necessity  be 
formed  after  the  lapse  of  time  and  will  be  based  upon 
the  experiences  of  many  trustworthy  observers  in  dif- 
ferent parts  of  the  country.  Nevertheless,  the  re- 
sults thus  far  achieved  in  the  saving  of  life  give 
promise  of  a  most  favorable  verdict.  In  the  follow- 
ing table  are  summarized  the  results  of  sero-therapy 
in  pneumonia  caused  by  type  I,  as  collected  from 
the  literature: 


TREATMENT  OF  PNEUMONIA  53 

TABLE  VIII 
Showing  Results  of  Sero-therapy  in  Pneumonia 


Investigator        < 

Number  of 
eases  treated 

Number  of 
recoveries 

Number  of 
deaths 

Number  of 
moribund  cases 
when  treatment 

was  begun 

Bloomfield 

II 

8 

3 

2 

Bovaird 

27 

22 

5 

3 

Christian 

14 

12 

2 

Cole 

105 

97 

8 

3 

Cole 

8 

8 

Litchfield 

12 

7 

5 

5 

McLelland 

13 

12 

I 

Spooner 

15 

14 

I 

I 

Thomas 

50 

47 

3 

3 

Total 

255 

227 

28 

17 

Of  the  255  patients  treated  with  serum,  227  re- 
covered and  28  died.  Seventeen  of  the  fatal  cases 
were  moribund  at  the  time  of  treatment,  so  that  fail- 
ure cannot  properly  be  ascribed  to  sero-therapy.  If 
the  17  unfavorable  cases  be  disregarded,  there 
remains  a  total  of  238  treated  cases  with  1 1  deaths  or 
a  mortality  of  4.6%.  The  mortality  of  untreated 
cases,  as  indicated  in  a  previous  table,  reaches  28.1%. 
The  mortality  is  almost  seven  times  higher  in  the  un- 
treated than  in  the  treated  cases  of  pneumonia  of 
type  I. 

Now  the  administration  of  horse  serum,  intra- 
vaneously,  may  be  attended  with  symptoms  of 
anaphylactic  shock.  This  results  from  the  parenteral 
introduction  of  foreign  proteins  in  those  subjects  who 
are  peculiarly  sensitive.  This  phenomenon  is  not 
limited  to  antipneumococcus  serum,  for  it  is  occasion- 
ally seen  after  the  use  of  diphtheria  antitoxin.    The 


54  RECENT  CLASSIFICATION  AND 

symptoms  are  varied,  and  include  suffusion  of  the  face, 
restlessness,  tachycardia,  urticaria,  and  collapse.  A 
history  of  asthma  or  of  hay-fever  in  the  patient  in- 
vites caution.  Irrespective  of  history,  the  cutaneous 
test  for  the  detection  of  protein  sensitization  may  well 
be  applied  as  a  preliminary  measure.  The  test  is 
similar  to  the  Von  Pirquet  test,  the  horse  serum 
being  substituted  for  the  tuberculin.  In  case  of  sen- 
sitiveness to  foreign  protein,  an  erythema  and  a 
localized  area  of  oedema  appears  at  the  site  of  in- 
jection within  an  hour.  In  order  to  desensitize  pa- 
tients, even  those  who  do  not  react  to  the  cutaneous 
test,  O.Sc.c.  to  Ic.c.  of  horse  serum  is  administered  sub- 
cutaneously  one-half  to  one  hour  before  the  intra- 
venous injection.  Another  good  rule  to  follow  is 
to  allow  15  minutes  for  the  injection  of  the  first  15c. c. 
of  serum.  If  the  patient  reacts  to  the  skin  test,  de- 
sensitization  may  be  accomplished  by  giving  small 
doses,  l-40c.c.,  which  are  gradually  increased. 

Of  greater  concern  are  the  symptoms  of  non-speci- 
fic serum  intoxication,  which  are  similar  to  those  seen 
in  the  administration  of  salvarsan.  These  may  appear 
during  the  treatment  or  may  come  on  an  hour  or  two 
afterwards.  The  symptoms  resemble  those  of  ana- 
phylactic shock  and  may  include  in  addition  vomit- 
ing, sweating,  and  high  rise  of  temperature.  To 
minimize  these  alarming  effects,  the  slow  injection 
of  the  serum,  maintained  at  body  temperature,  be- 
comes imperative.  The  administration  of  the  serum 
may  have  to  be  interrupted,  and  resumed  an  hour  or 
two  later.  Adrenalin  and  atropin  happily  afford 
prompt  relief. 


TREATMENT  OF  PNEUMONIA  55 

Unlike  anaphylaxis  and  non-specific  serum  in- 
toxication, the  symptoms  of  serum  sickness  appear 
delayed, —  from  seven  to  fourteen  days  after  the  ad- 
ministration. The  latter  are  characterized  by  ele- 
vation of  temperature,  skin  rashes,  glandular  en- 
largement, and  joint  pains.  They  are  never  serious. 
Urticaria  is  the  most  common  manifestation,  and 
it  is  readily  controlled  by  adrenalin  and  carbolic 
washes. 

The  encouraging  results  of  antipneumococcus 
serum  I  in  therapy  have  been  disclosed  by  the  fore- 
going analysis  of  available  data.  Statistics  have 
furthermore  shown  a  percentage  incidence  of  type  I 
infections  amounting  to  29.6.  This  equals  the  in- 
cidence of  pneumonia  caused  by  the  other  two  "fixed 
types"  of  pneumococcus,  types  II  and  III.  Serum 
from  animals,  actively  immunized  against  these  two 
types,  has  proven  of  no  value  in  treatment  of  pneu- 
monia. To  offset  this  failure,  Humbert  has  made  a 
most  excellent  suggestion,  which  merits  serious  con- 
sideration. He  has  proposed  the  "endless  chain" 
treatment  of  pneumonia.  He  avails  thereby  of  the 
immune  bodies  which  are  present  in  the  serum  of 
those  persons  who  have  recovered  from  the  disease. 
Convalescents  are  bled.  The  serum  is  pipetted  off 
after  clotting  has  taken  place  and  centrifuged.  It 
is  next  inactivated  by  heating  to  36°C.  for  thirty 
minutes.  Tricresol  (3-10  of  1%)  is  added  as  a  pre- 
servative. The  serum  is  kept  in  stock,  properly  la- 
belled so  as  to  indicate  the  type  of  pneumococcus  in- 
fection  from   which    the    donor   has   recovered.    In 


56  RECENT  CLASSIFICATION  AND 

treatment,  the  type  of  pneumococcus  causing  the 
pneumonia  is  determined,  and  the  appropriate  serum 
is  administered  intravenously,  type  for  type. 

Humbert  reports  that  of  11  cases  treated  in  this 
manner,  one  death  occurred  in  a  type  III  infection. 
The  incidence  of  types  in  his  series  was  as  follows : 
Type  I,  2  cases;  type  II,  4  cases;  type  III,  4  cases; 
and  type  IV,  1  case.  The  number  is  too  small  to 
admit  of  definite  conclusions.  Nevertheless,  anal- 
ogous experiences  during  the  pandemic  of  influenza 
indicate  that  the  use  of  human  convalescent  serum 
in  acute  pulmonary  infections  is  attended  with  bene- 
ficial  results. 

McGuire  and  Redden  have  treated  151  patients 
with  influenzal  pneumonia  by  intravenous  injections 
of  human  convalescent  serum.  Of  this  number  only 
six  died,  giving  a  mortality  of  4%.  O'Malley  and 
Hartman  have  had  similar  gratifying  results  in  the 
treatment  of  influenzal  pneumonia  by  the  same 
method.  Only  three  deaths  occurred  in  46  treated 
cases,  making  a  mortality  of  6.5%;  whereas  of  111 
untreated  patients,  28  died,  yielding  a  mortality  per- 
centage of  25.2. 

The  cause  of  influenza  has  not  yet  been  definitely 
established.  Nevertheless,  patients  recovering  from 
the  infection  have  in  their  blood  stream  antibodies 
which  are  capable  of  conferring  passive  immunity. 
It  is  not  unreasonable  to  suppose,  therefore,  that 
serum  obtained  from  patients  who  have  recovered 
from  type  II  and  type  III  pneumonia  may  likewise 
have   protective    bodies.    At    least    Humbert's   sug- 


TREATMENT  OF  PNEUMONIA  57 

gestlon  may  well  be  tried  until  potent  antisera  are 
experimentally  produced. 

Sufficient  time  has  now  elapsed  to  justify  the  use 
of  vaccines  as  a  prophylactic  against  some  bacterial 
infections.  It  has  seemed  inevitable  that  their  use 
be  extended  to  the  treatment  of  disease.  Some  ob- 
servers maintain  that  active  immunization  with  a 
pneumococcus  vaccine  is  of  value  in  the  treatment  of 
pneumonia.  Accordingly,  Rosenow  has  suggested  the 
vaccine  treatment  of  pneumonia  for  the  type-cases 
for  which  there  is  no  antiserum  available.  Pneumo- 
coccus vaccine,  extensively  employed  in  former  years, 
is  at  present  in  disrepute  as  a  therapeutic  agent.  The 
cause  of  failure  has  been  attributed  to  the  toxic  ma- 
terial which  is  present  in  heat-killed  pneumococcic 
vaccine.  Rosenow  has  consequently  devised  a  vac- 
cine of  partially  autolyzed  pneumococci.  He  elimi- 
nates the  toxic  fraction  of  the  bacterial  cells  and 
retains  the  antigenic  fraction.  Virulent  strains  of  the 
organisms  are  grown  in  glucose  broth  from  18  to  24 
hours.  A  suspension  of  the  sediment,  obtained  by 
centrifugalization,  is  made  with  salt  solution.  The 
suspensions  from  various  strains  are  mixed  in  bottles 
to  which  a  small  amount  of  ether  is  added.  The  bot- 
tles are  thoroughly  shaken  and  incubated  for  three  to 
five  days.  During  the  period  of  incubation,  the 
bottles  are  shaken  twice  daily.  Each  day  a  small 
quantity  of  the  suspension  is  removed  and  a  current 
of  air  is  passed  through  the  mixture  to  displace  the 
ether.  Slides  are  made  from  the  suspension  and 
stained.    Incubation  is  discontinued  when  95%  of  the 


58  RECENT  CLASSIFICATION  AND 

organisms  become  Gram  negative,  and  when  5c. c.  of 
the  suspension  cause  no  toxic  symptoms  in  guinea 
pigs. 

The  Rosenow  vaccine,  therefore,  differs  from 
others  in  that  it  does  not  consist  of  an  emulsion  of  or- 
ganisms killed  by  heat,  but  of  an  emulsion  of  organ- 
isms which  have  undergone  partial  digestion.  One 
cubic  centimetre  of  the  vaccine,  containing  200 
billion  organisms,  is  administered  daily  until  the 
temperature  becomes  normal  and  remains  normal  for 
one  to  two  days. 

Rosenow  has  employed  his  vaccine  in  the  treat- 
ment of  200  cases  of  lobar  pneumonia.  Of  this 
number,  186  have  recovered  and  14  have  died.  In 
the  186  cases  of  recovery,  there  have  been  strikingly 
good  results  in  63,  good  in  73,  and  indifferent  in  50. 
Furthermore,  the  average  mortality  rate  in  95  pa- 
tients receiving  the  vaccine  early  in  the  disease  was 
3%;  and  in  the  105  cases  receiving  the  first  injection 
on  the  third  day  of  the  disease  or  later,  was  11%.  The 
average  mortality  of  all  cases  treated  was  7%. 

The  mode  of  action  of  this  vaccine  is  still  obscure. 
Further  experience  will  determine  the  usefulness  of 
active  immunization  in  the  treatment  of  acute  in- 
fectious diseases.  In  this  regard,  the  opinion  of 
Theobald  Smith  is  as  important  as  it  is  authoritative 
— "vaccines  applied  during  disease  will  be  rarely,  if 
ever,  life  saving,  but  they  may  hurry  a  stationary  or 
languid  process  which  tends  towards  recovery,  by 
bringing  into  play  the  unused  reserve  of  various 
tissues." 


TREATMENT  OF  PNEUMONIA  59 

Before  the  advent  of  serum  and  vaccine  therapy, 
the  treatment  of  pneumonia  depended  upon  the  no- 
tions of  the  individual  practitioners.  Search  was 
made  in  vain  for  a  specific  remedy.  Drug  after  drug 
was  tried.  During  my  interneship,  a  routine  treat- 
ment for  pneumonia  was  the  administration  of  10 
grains  of  quinine  every  two  hours  for  six  doses.  The 
temperature  on  the  day  following  the  treatment  in- 
variably came  down  to  normal,  but  soon  became 
elevated.  The  course  of  the  disease  was  otherwise 
unaffected.  The  discovery  of  optochin,  a  derivative 
of  quinine,  by  Morgenroth  and  Levy,  in  1911,  be- 
came, therefore,  a  matter  of  unusual  interest.  These 
investigators  found  that  optochin  possessed  a  specific 
bacteriocidal  action  on  pneumococci  both  in  vitro 
and  vivo.  Hopes  were  aroused  that  the  drug  might 
prove  of  value  in  therapy.  The  results  obtained  in 
the  treatment  of  75  cases  of  pneumonia  at  the 
Rockefeller  Hospital  with  optochin  were  disappoint- 
ing.   No  beneficial  results  were  noted. 

However,  the  combined  use  of  optochin  and  im- 
mune sera  in  experimental  pneumococcic  infections 
has  proved  more  effective  than  if  either  one  were  em- 
ployed singly.  It  seems  as  if  optochin  enhances  the 
action  of  immune  serum.  Moore  has  demonstrated 
this  property  of  the  drug  by  the  use  of  mice.  One- 
half  cubic  centimetre  of  a  2%  oily  solution  of  op- 
tochin and  0.2c.c.  of  antiserum  II  each  fail  to  protect 
a  mouse  against  0.06c.c.  of  a  highly  virulent  culture 
of  pneumococcus  type  II.  Now  if  the  optochin  and 
immune    serum    are    injected    simultaneously,    pro- 


60  RECENT  CLASSIFICATION  AND 

tection  is  afforded  the  animal  against  O.Sc.c.  of  culture 
—  or  eight  times  the  amount  of  culture  against 
which  each  alone  would  be  ineffective.  Chemosero- 
therapy  still  remains  an  inviting  field  for  investiga- 
tion. The  success  which  has  attended  the  use  of 
salvarsan  lends  encouragement  to  the  search  for 
chemo-bacteriocidal  agents  in  vivo. 

The  pneumococcidal  property  of  optochin  has, 
furthermore,  suggested  its  use  in  prophylaxis.  Kolmer 
and  Steinfeld  recommend  a  1:10,000  solution  of  op- 
tochin in  a  1 :10  liquor  thymolis,  as  a  gargle  or  mouth 
wash.  They  are  of  the  opinion  that  such  a  solution 
"may  ser\'e  to  destroy  virulent  pneumococci  as  they 
gain  access  to  the  mucous  membrane  of  the  mouth 
and  upper  part  of  the  throat  and  prevent  their  pro- 
liferation in  large  numbers."  The  liability  to  in- 
fection with  pneumococci  by  contact  has  been  pre- 
viously indicated.  This  liability  would,  therefore, 
be  appreciably  lessened  if  systematic  gargling  with 
the  optochin  solution  were  adopted  by  physicians, 
nurses,  and  members  of  the  family  of  a  patient 
stricken  with  pneumonia.  The  application  might 
also  be  extended  to  convalescents  of  the  disease. 

The  studies  of  the  last  decade  have  resulted  in  a 
better  understanding  of  pneumonia,  caused  by  the 
pneumococcus.  The  results  achieved  in  the  classifi- 
cation and  treatment  of  this  disease  may  be  pre- 
cursive  of  still  more  effective  measures  in  the  con- 
servation of  human  life. 


TREATMENT  OF  PNEUMONIA  61 

NOTE.  The  writer  has  drawn  freely  upon  the 
recent  Hterature  bearing  upon  the  subject  matter 
of  this  thesis,  and  has  been  bold  enough  to  include  his 
experience  and  suggestions.  Full  acknowledgments 
are  made  to  the  investigators  mentioned,  by  whose 
toil  medical  science  has  been  enriched. 


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